This invention relates to a compound for replacing or reconstructing rigid or semi-rigid living tissue. More particularly, the present invention relates to a compound comprising biodegradable poly(propylene fumarate) networks, which may be crosslinked with diacrylate macromers, and a method for making same.
In the field of tissue engineering, degradable biomaterials usually serve as a scaffold to provide mechanical support and a matrix for the ingrowth of new tissue. As new tissue forms on the scaffold, the biomaterial degrades until it is entirely dissolved. The degradation products are eliminated through the body""s natural pathways, such as metabolic processes.
One example of the use of such biomaterials is as a temporary bone replacement. It is often desired to replace or reconstruct all or a portion of a living bone, such as when a bone has been broken or has been resected as a result of a bone tumor. In these instances, the missing bone can be replaced with a mechanical device, such as a pin, plate or the like, or it can be replaced with an implant that is designed to more closely resemble the original bone itself. Often these implants comprise biodegradable polymeric compounds or parts made from such compounds. It is contemplated that bone tissue will grow back into the pores of the implant and will gradually replace the entire implant as the implant itself is gradually degraded in the in vivo environment. For obvious reasons then, such implants should be biocompatible and non-toxic.
Similarly, the use of biodegradable polymers for temporary surgical and pharmacological applications such as drug delivery has been explored recently. Aliphatic polyesters and anhydrides are the polymer families that have been recognized as the most attractive and promising.
Poly(propylene fumarate) (PPF) is one such polymer. Poly(propylene fumarate) (hereinafter xe2x80x9cPPFxe2x80x9d) is an unsaturated linear polyester that degrades in the presence of water into propylene glycol and fumaric acid, degradation products that are easily cleared from the human body by normal metabolic processes. Because the fumarate double bonds in PPF are reactive and crosslink at low temperatures, it has potential to be an effective in situ polymerizable biomaterial. The crosslinking reaction can be carried out at a defect site using a benzoyl peroxide initiator, which is particularly interesting for orthopaedic applications in filling irregularly shaped defects with minimal surgical intervention. Several PPF-based formulation methods have been evaluated by varying such parameters as the molecular weight of PPF and the choice of crosslinking reagents. For example, U.S. Pat. No. 5,733,951 discloses a composite mixture incorporating P(PF), a crosslinking monomer (N-vinyl pyrrolidone), a porogen (sodium chloride), and a particulate phase (xcex2-tricalcium phosphate) that can be injected or inserted into skeletal defects of irregular shape or size.
As in the ""951 patent, much of the previous work involving PPF used n-vinyl pyrrolidone (NVP) as a crosslinking reagent. The crosslinking agent bonds at its ends to separate, larger propylene fumarate molecules, serving as a link or bridge between them. While these compounds exhibit promising characteristics, it is believed preferable to avoid the presence of any unreacted NVP after in situ polymerization. Also, the poly(vinyl pyrrolidone) (PVP) links in the crosslinked PPF networks are non-degradable.
It is possible to use poly(ethylene glycol)-dimethacrylate (PEG-DMA) as a crosslinking reagent to form PPF polymer networks. PPF/PEG-DMA composites appear to posses ideal initial mechanical properties. These desired properties decrease in the wet state, however, due to the hydrophilicity of PEG. Hence, in order to retain the favorable mechanical properties, it is desirable to avoid high degrees of water absorption.
Another important factor in the success of biomaterials development is the nature of the degradation products. Although degradation of PPF-based polymer composites has been studied to assess the mass loss and the change of mechanical properties, the degradation products have not been characterized.
Hence, it is desired to provide biodegradable PPF-based polymer networks that do not require the use of NVP, are biodegradable, have desired mechanical properties in both dry and wet states, and that degrade into non-toxic degradation products.
The present invention includes the use of PPF-diacrylate (PPF-DA) as a crosslinking reagent in the polymerization of PPF. As discussed below, the effects of double bond ratio of PPF/PPF-DA and molecular weight of PPF-DA on the mechanical properties of the crosslinked polymer networks as well as on their equilibrium water content have been evaluated. It has been discovered that the degradation reaction of the PPF/PPF-DA polymer networks yields degradation products that are non-toxic and readily metabolized. The present invention includes methods for make novel compounds, including polymeric networks consisting essentially of cross linked PPF, poly(propylene fumarate) networks cross linked with diacrylate, cross linkable compositions comprising PPF-DA, and poly(propylene fumarate) networks crosslinked with diacrylate macromers. The inventive methods include making a polymer network by forming propylene fumarate (PF) by the reaction of fumaryl chloride with propylene glycol, transesterifying the PF to give PPF, synthesizing PPF-DA by reacting the PPF with an acrylation reagent; and cross-linking the PPF-DA, as well as the intermediate steps of this process.
As used herein, the term xe2x80x9cnetworkxe2x80x9d refers to polymeric molecules that have been cross linked so as to effectively form a continuous molecule. The term xe2x80x9cgelxe2x80x9d is sometimes used to refer to the same type of cross linked systems.